NEW YORK—An anti-angiogenic copper chelator continues to show remarkable success in preventing relapse in women with high-risk triple-negative breast cancer, according to data presented here at the Chemotherapy Foundation Symposium.
“This is potentially a very exciting advance for women who are at the highest risk of recurrence of breast cancer,” Linda Vahdat, MD, Professor and Director of the Breast Cancer Research Program and Chief of the Solid Tumor Service at Weill Cornell Medical College, said in an interview after her presentation.
Several of the participants in the study she described with a history of metastatic triple-negative breast cancer have had long-term benefit, remaining disease free for three to five and a half years.
Despite improvements in breast cancer therapy, there remains a significant risk of relapse in a high-risk subset of patients. The risk of relapse in stage 3 patients is 50 to 75 percent over five years, and patients with stage 4 breast cancer always recur, she noted. Triple-negative breast cancer patients has a poorer prognosis even when diagnosed at an early stage.
“Triple-negative patients represent a substantial proportion of metastatic breast cancer patients. These are the patients who need the most attention.”
Vahdat, who is also a medical oncologist at the Iris Cantor Women's Health Center at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, explained that the anti-copper compound appears to be keeping tumors that want to spread in a dormant state. “It appears to affect the tumor microenvironment, specifically the bone marrow-derived cells that are critical for metastasis progression.”
Weill Cornell researchers have found that a collection of bone marrow-derived cells, which include VEGFR1+ hematopoietic progenitor cells (HPCs), prepare a site in distant organs to accept cancer cells. HPCs also recruit endothelial progenitor cells (EPCs), among others, to activate an “angiogenic switch” that establish blood vessels at the site to feed newly migrated cancer cells.
In breast cancer patients, there is a higher level of EPCs and HPCs with increasing stage. Immediately prior to cancer relapse, levels of EPCs and HPCs rise significantly further, suggesting that the EPC target of the copper-depletion approach is one that makes sense, she said. “Breast tumors want to move to specific organs, and these EPCs and HPCs leave a trail for cancer cells to follow, as well as provide the building blocks for blood vessels to greet them as they arrive.”
Phase II Study Results
Is it possible to impact the EPCs—that is, the microenvironment—in a high-risk population? Vahdat and her colleagues devised a Phase II study to answer that question. Breast cancer patients who were at high-risk of relapse received tetrathiomolybdate (TM) as a chemopreventive agent. TM is a copper chelation compound used to treat Wilson's disease, a hereditary copper metabolism disorder, and has been studied in Phase I and Phase II clinical trials for several disorders. Animal studies have demonstrated that depleting copper decreases the proliferation of EPCs, as well as blood vessel formation and tumor growth, she noted.
“Copper is essential for angiogenesis. It is a required co-factor for activators of angiogenesis. Copper-dependent enzymes are critical for priming the pre-metastatic niche. Copper also affects the migration and invasion of endothelial cells. Perhaps copper depletion prevents transition to micrometastases.
The open-label, single-arm Phase II trial has enrolled 69 patients so far. These women have a high risk of relapse from occult residual disease, including histologically confirmed stage III disease, stage IV breast cancer with no evidence of disease (NED), and stage II triple-negative breast cancer. More than six weeks after their previous chemotherapy, the patients had no radiographic, biochemical, or physical evidence of recurrence.
Two phases of tetrathiomolybdate were administered: The first phase was to induce a target level of serum ceruloplasmin (Cp), a surrogate marker of copper availability. The second was to maintain that level. During the induction phase, TM at 180 mg daily was administered until Cp levels reached a target range of 5 to 16 mg/dL. Serum was tested every two weeks for the first month and weekly thereafter until the target was reached.
During the maintenance phase, TM at 100 mg daily was administered to maintain the Cp level below 17 mg/dL for two years or until relapse. Dosing was reduced or increased in 20 mg increments to control toxic effects, and patients were taken off the study drug if they experienced unacceptable toxicity.
Vahdat and her colleagues reported earlier this year (Annals of Oncology 2013; 24:1491-1498, Sarika Jain first author) that three-quarters of patients reached the target copper-depletion level by one month. The study showed a significant, sustained reduction in EPCs with copper depletion. EPCs did not significantly change in patients unable to achieve or maintain the Cp target.
“Copper depletion may inhibit the production, release, or mobilization of EPCs from the bone marrow, leading to suppression of the angiogenic switch and tumor dormancy,” Vahdat said.
Although the effect of copper depletion on HPCs and circulating markers of angiogenesis was not significant, previous studies have shown that HPCs predict relapse and progression of disease, suggesting that these cells are important, but perhaps earlier in the metastatic cascade.
Overall, TM therapy was well tolerated; the only grade 3 or 4 toxic effects were hematologic, including grade 3/4 neutropenia, grade 3 leukopenia, grade 3 anemia, and febrile neutropenia.
The association between decreases in Cp and decreases in the number of EPCs was stronger in triple-negative patients. “Angiogenesis-related genes are frequently overexpressed in triple-negative tumors, and anti-angiogenic agents may be more effective in this subset,” she noted.
At the Symposium, Vahdat presented data on the first 43 patients, median age of 49, who have completed two years of therapy. More than two-thirds were treated in the adjuvant setting, and one-third of these patients had triple-negative disease.
In this group, TM reduced copper levels by a mean of 50 percent, which was sustained over time. “Copper depletion was most effective in the triple-negative breast cancer patients,” she said, adding that EPCs decreased only in copper-depleted patients.
After a median follow-up of 4.5 years, progression-free survival (PFS) was estimated at 84 percent. There were no differences in PFS between nodal status or molecular subtypes, and no relapses occurred after 10 months for those who achieved PFS. Importantly, PFS was seen in about two-thirds of triple-negative patients classified as with stage 4 no evidence of disease (NED). The estimated overall survival was 90.6 percent after a median follow-up of 4.5 years.
Two patients who were not copper-depleted had a disease recurrence—one patient at cycle 2 and the other at cycle 10.
“We went back to the bench to determine the effect of TM on the pre-metastatic niche. As in the clinical trial, in a triple-negative breast cancer cell line, TM had a marked effect in reducing metastases,” Vahdat said.
She and her colleagues continue to accrue patients into the trial—up to 80 patients—and the study has been extended to six years in selected patients. “We will continue to analyze and model the data. We are dissecting out the effect of TM on lung metastases and the pre-metastatic niche. As the evidence accumulates in favor of copper depletion to prevent relapse, we plan to organize a large, randomized, multicenter trial enriched with triple-negative and stage 4 NED patients.”
She added: “Keeping cancer dormant is what we all want for our patients—especially triple-negative breast cancer patients at highest risk of recurrence.”
‘Taking Different Approach to Angiogenesis’
Asked for his opinion for this article, session moderator Harold Burstein, MD, PhD, Associate Professor of Medicine at Harvard Medical School and a clinical investigator in the Breast Oncology Center at Dana-Farber Cancer Institute and Brigham and Women's Hospital, said, “This is a nice piece of clinical work that shows promise. We will see what comes of it in more trials.
“The Weill Cornell researchers are taking a different approach to angiogenesis. They are looking at a way to block the establishment of metastasis in the first place. This is a unique mechanism of action and different from most angiogenesis trials. It has interesting implications, particularly for triple-negative breast cancer patients.”
He noted, though, that it is difficult to conduct such an investigation without pharmaceutical company support—“it is difficult to get funding or attention, but this concept does need exploring.”